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Evolutionary genetics

Host–pathogen interactions shape human evolution and future pandemics

Nature Reviews Genetics volume 27, page 115 (2026)Cite this article

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As the causative agents of infectious diseases, pathogens have been a major threat to human health and survival throughout our history. Consequently, pathogen infections have shaped human evolution — a notion that has existed at least since the late 1940s, when Haldane suggested that the prevalence of certain inherited blood disorders is linked to selection exerted by malaria. Testing such hypotheses was one of the many applications of the genomics revolution that provided genomes from diverse species and human individuals, which indeed helped identify various evolutionary trends in genes related to immune defence and pathogen infection. However, it was not immediately clear how evolutionary changes in our genome, driven by past selection, mechanistically affect our ability to resist present-day pathogens.

The authors sequenced TRIM5 orthologues across the primate clade, to which they applied several codon-based evolutionary models to infer the selective pressures that have acted on this gene. Interestingly, this analysis found compelling evidence for positive selection in almost one-fifth of the TRIM5 codons, indicating that the resulting many amino acid substitutions between primates may confer a selective advantage. Following this result, the authors sought to functionally test how these differences in TRIM5 orthologues influence HIV-1 replication. To do so, they overexpressed (in a feline cell line permissive of HIV-1 replication) variants of TRIM5, including the human and macaque orthologues, as well as chimeras where many of the positively selected sites were swapped. These experiments showed that overexpressing the macaque orthologue substantially decreased HIV-1 replication (relative to no TRIM5 overexpression), whereas overexpressing the human orthologue also caused a decrease but to a lesser extent. Importantly, overexpressing the chimeras showed that the swapped region — with many of the positively selected sites — is largely responsible for the difference between human and macaque TRIM5 in reducing HIV-1 replication.

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References

Original article

  • Sawyer, S. L. et al. Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain. Proc. Natl Acad. Sci. USA 102, 2832–2837 (2005)

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  1. Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv, Israel

    Tzachi Hagai

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  1. Tzachi Hagai
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Correspondence to Tzachi Hagai.

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The author declares no competing interests.

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Hagai, T. Host–pathogen interactions shape human evolution and future pandemics. Nat Rev Genet 27, 115 (2026). https://doi.org/10.1038/s41576-025-00902-6

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